Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia--Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with hypoxia, anoxia, or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
It is known that compounds of various structures, such aminophosphonovalerate derivatives and piperidine dicarboxylate derivatives, may act as competitive antagonists at the NMDA receptor and also block the increase in cyclic GMP levels due to the presence of excitatory amino acids [P. L. Wood et al, Neuropharm., 21, 1235-1238 (1982)].
Certain piperidineethanol derivatives, such as ifenprodil and (.+-.)-.alpha.-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]-1-piperidineeth anol, which are known anti-ischemic agents, have been found to be non-competitive NMDA receptor antagonists which also block the increase of cyclic GMP levels due to the presence of excitatory amino acids [C. Carter et al, J. Pharm Exp. Ther., 247 (3), 1222-1232 (1988)].
Ethanoanthracene-type compounds have been identified for other pharmaceutical uses. For example, tricyclic oligoamine compounds, such as N,N'-bis-(4-phenylbutyl)-9,10-dihydro-9,10-ethanoanthracene-11,12-bis-meth ylamine, have been mentioned for use as inhibitors of platelet aggregation (K. Rehse et al, Arch. Pharm. (Neinheim), 320, 829-836 (1987)]. A class of dihydro-9,10-ethano-9,10-anthracene compounds, including 9,10-dihydro-1,2-(1-pyrrolidinylmethyl)-9,10-ethanoanthracen-11-one, have been evaluated for analgesic activity [S. Lecolier, Chim. Ther., 3, 34-38 (1968)]. Certain 9,10-dihydro-9,10-ethanoanthracene derivatives, including N-(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-N,N',N'-trimethylethylenedi amine, 4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-methylpiperizine and 1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine have been described as having anticholinergic, antihistaminic, local anesthetic or hypotensive properties [J. R. Boissier et al, J. Med. Chem., 10, 86-91 (1967)]. U.S. Pat. No. 3,422,104 describes 9,10-dihydro-9,10-ethanoanthracene compounds, including N-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]dimethylamine, 4-[(9,10-dihydro-9,10-ethanoanthracenyl)-methyl]-1-(2 -hydroxyethyl)piperizine and 1-[(9,10-dihydro-9,10-ethanoanthracenyl)-ethyl]piperidine for use as a spasmolytic or in treatment of depression. Swiss Patent No. 482,642 describes certain 11-aminoalkyl-9,10-dihydro-9,10-ethanoanthracenes, including N-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]methylamine, 4-methylpiperazide of 9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid and 1-[(9,10-dihydro-9,10-ethanoanthracenyl)ethyl]piperidine as anesthetics.